Influencing factors on the safety and effectiveness of venom immunotherapy.

BACKGROUND AND OBJECTIVE: The safety profile of venom immunotherapy (VIT) is a relevant issue and considerable differences in safety and efficacy of VIT have been reported. The primary aim of this study was to evaluate the safety of ACE inhibitors and beta-blockers during VIT, which has already been published. For a second analysis, data concerning premedication and venom preparations in relation to systemic adverse events (AE) during the up-dosing phase and the first year of the maintenance phase were evaluated as well as the outcome of field stings and sting challenges. METHODS: The study was conducted as an open, prospective, observational, multicenter study. In total, 1,425 patients were enrolled and VIT was performed in 1,342 patients. RESULTS: Premedication with oral antihistamines was taken by 52.1% of patients during the up-dosing and 19.7% of patients during the maintenance phase. Taking antihistamines had no effect on the frequency of systemic AE (p=0.11) but large local reactions (LLR) were less frequently seen (OR: 0.74; 95% CI: 0.58-0.96; p=0.02). Aqueous preparations were preferentially used for up-dosing (73.0%) and depot preparations for the maintenance phase (64.5%). The type of venom preparation neither had an influence on the frequency of systemic AE nor on the effectiveness of VIT (p=0.26 and p=0.80, respectively), while LLR were less frequently seen when depot preparations were used (p<0.001). CONCLUSION: Pretreatment with oral antihistamines during VIT significantly reduces the frequency of LLR but not systemic AE. All venom preparations used were equally effective and did not differ in the frequency of systemic AE.

Dietary carbohydrate influences the colocalization pattern of Glucagon-like Peptide-1 with neurotensin in the chicken ileum.

Glucagon-like peptide (GLP)-1 colocalizes with neurotensin (NT) in the same enteroendocrine cells (EECs) of the chicken ileum. The present study was designed to clarify the influence of dietary carbohydrate (CHO) on the colocalization pattern of GLP-1 with NT in the chicken distal ileum. Male White Leghorn chickens at 6 weeks of age (n = 15) were divided into three groups, a control and two experimental (low-CHO and CHO-free), with five chickens in each, and fed control or experimental diets for 7 d. Distal ileum was collected from each bird as a tissue sample and subjected to double immunofluorescence staining to detect GLP-1 and NT. Three types of EEC, GLP-1+/NT+, GLP-1+/NT- and GLP-1-/NT+, were demonstrated in the chicken ileum. GLP-1+/NT+ cells in the control group had a spindle-like shape with a long cytoplasmic process, but those in the experimental groups were round and lacked a cytoplasmic process. The ratio of GLP-1+/NT+ cells was significantly decreased in the two experimental groups compared with that in the control group. The ratio of GLP-1+/NT+ cells was significantly lower than those of GLP-1+/NT- and GLP-1-/NT+ cells in the two experimental groups. Most cells that were immunoreactive for GLP-1 and NT antisera lacked signals of proglucagon (PG) and NT precursor (NTP) mRNA in the experimental groups. The number of EECs expressing PG and NTP mRNA signals showed tendencies for decreases with a reduction of dietary CHO level. These findings suggest that dietary CHO could be a significant regulator of the pattern of colocalization pattern of GLP-1 with NT in the chicken ileum.

Impact of training of mothers, drug shop attendants and voluntary health workers on effective diagnosis and treatment of malaria in Lagos, Nigeria.

BACKGROUND: The National Malaria Eradication Program and international agencies are keen on scaling up the use of malaria rapid diagnostic tests (mRDTs) and artemisinin-based combination therapies (ACTs) for effective diagnosis and treatment of the disease. However, poor diagnostic skills and inappropriate treatment are limiting the efforts. In Nigeria, a large proportion of infected patients self-diagnose and treat while many others seek care from informal drug attendants and voluntary health workers. AIMS: This study describes the impact of training voluntary health workers, drug shop attendants, and mothers on effective case detection and treatment of malaria in Lagos, Nigeria. METHODS: We trained mothers accessing antenatal care, drug shop attendants, and voluntary health workers selected from the three districts of Lagos, on the use of histidine-rich protein-2-based mRDTs and ACTs. Pre- and post-training assessments, focus group discussions (FGDs), and in-depth interviews (IDIs) were carried out. RESULTS: The knowledge, attitude, and skill of the participants to achieve the goal of "test, treat, and track" using mRDT and ACTs were low (11%-55%). There was a low awareness of other non-malaria fevers among mothers. Self-medication was widely practiced (31.3%). FGDs and IDIs revealed that health-care providers administered antimalarials without diagnosis. Training significantly improved participants' knowledge and expertise on the use of mRDTs and ACTs (P = 0.02). The participants' field performance on mRDT use was significantly correlated with their category (bivariate r = 0.51, P = 0.001). There was no statistically significant association between the participants' level of education or previous field experience and their field performance on mRDT (r = 0.12, P = 0.9; χ 2= 38, df = 2 and P = 0.49). CONCLUSION: These findings suggest that training of stakeholders in malaria control improves diagnosis and treatment of malaria. However, a broader scope of training in other settings may be required for an effective malaria control in Nigeria.

Co-active receptor tyrosine kinases mitigate the effect of FGFR inhibitors in FGFR1-amplified lung cancers with low FGFR1 protein expression.

Targeted therapies are effective in subsets of lung cancers with EGFR mutations and anaplastic lymphoma kinase (ALK) translocations. Large-scale genomics have recently expanded the lung cancer landscape with FGFR1 amplification found in 10-20% of squamous cell carcinomas (SCCs). However, the response rates have been low for biomarker-directed fibroblast growth factor receptor (FGFR) inhibitor therapy in SCC, which contrasts to the relatively high rates of response seen in EGFR mutant and ALK-translocated lung cancers treated with epidermal growth factor receptor (EGFR) inhibitors and ALK inhibitors, respectively. In order to better understand the low response rates of FGFR1-amplified lung cancers to FGFR inhibitors, relationships between gene copy number, mRNA expression and protein expression of FGFR1 were assessed in cell lines, tumor specimens and data from The Cancer Genome Atlas. The importance of these factors for the sensitivity to FGFR inhibitors was determined by analyzing drug screen data and conducting in vitro and in vivo experiments. We report that there was a discrepancy between FGFR1 amplification level and FGFR1 protein expression in a number of these cell lines, and the cancers with unexpectedly low FGFR1 expression were uniformly resistant to the different FGFR inhibitors. Further interrogation of the receptor tyrosine kinase activity in these discordant cell lines revealed co-activation of HER2 and platelet-derived growth factor receptor-α (PDGFRα) caused by gene amplification or ligand overexpression maintained phosphoinositide 3-kinase (PI3K) and MEK/ERK signaling even in the presence of FGFR inhibitor. Accordingly, co-inhibition of FGFR1 and HER2 or PDGFRα led to enhanced drug responses. In contrast, FGFR1-amplified high FGFR1 protein-expressing lung cancers are sensitive to FGFR inhibitor monotherapy by downregulating ERK signaling. Addition of a PI3K inhibitor to these high FGFR1 protein-expressing cancers further sensitized them to FGFR inhibitor. These data reveal that biomarker-directed trials for FGFR1-amplified SCC require assessment of FGFR1 protein expression and uncover novel therapeutic strategies for FGFR1-amplified SCC with low FGFR1 protein expression.

Muscarinic acetylcholine receptor subtype 4 is essential for cholinergic stimulation of duodenal bicarbonate secretion in mice - relationship to D cell/somatostatin.

We investigated the roles of muscarinic (M) acetylcholine receptor subtype in the cholinergic stimulation of duodenal HCO3(-) secretion using knockout (KO) mice. Wild-type and M1-M5 KO C57BL/6J mice were used. The duodenal mucosa was mounted on an Ussing chamber, and HCO3(-) secretion was measured at pH 7.0 using a pH-stat method in vitro. Carbachol (CCh) or other agents were added to the serosal side. CCh dose-dependently stimulated HCO3(-) secretion in wild-type mice, and this effect was completely inhibited in the presence of atropine. The HCO3(-) response to CCh in wild-type mice was also inhibited by pirenzepine (M1 antagonist), 4DAMP (M3 antagonist), and tropicamide (M4 antagonist), but not by methoctramine (M2 antagonist). CCh stimulated HCO3(-) secretion in M2 and M5 KO animals as effectively as in WT mice; however, this stimulatory effect was significantly attenuated in M1, M3, and M4 KO mice. The decrease observed in the CCh-stimulated HCO3(-) response in M4 KO mice was reversed by the co-application of CYN154806, a somatostatin receptor type 2 (SST2) antagonist. Octreotide (a somatostatin analogue) decreased the basal and CCh-stimulated secretion of HCO3(-) in wild-type mice. The co-localized expression of somatostatin and M4 receptors was confirmed immunohistologically in the duodenum. We concluded that the duodenal HCO3(-) response to CCh was directly mediated by M1/M3 receptors and indirectly modified by M4 receptors. The activation of M4 receptors was assumed to inhibit the release of somatostatin from D cells and potentiate the HCO3(-) response by removing the negative influence of somatostatin via the activation of SST2 receptors.

Cyclic compressive loading on 3D tissue of human synovial fibroblasts upregulates prostaglandin E2 via COX-2 production without IL-1ß and TNF-α.

OBJECTIVE: Excessive mechanical stress on synovial joints causes osteoarthritis (OA) and results in the production of prostaglandin E2 (PGE2), a key molecule in arthritis, by synovial fibroblasts. However, the relationship between arthritis-related molecules and mechanical stress is still unclear. The purpose of this study was to examine the synovial fibroblast response to cyclic mechanical stress using an in vitro osteoarthritis model. METHOD: Human synovial fibroblasts were cultured on collagen scaffolds to produce three-dimensional constructs. A cyclic compressive loading of 40 kPa at 0.5 Hz was applied to the constructs, with or without the administration of a cyclooxygenase-2 (COX-2) selective inhibitor or dexamethasone, and then the concentrations of PGE2, interleukin-1ß (IL-1ß), tumour necrosis factor-α (TNF-α), IL-6, IL-8 and COX-2 were measured. RESULTS: The concentrations of PGE2, IL-6 and IL-8 in the loaded samples were significantly higher than those of unloaded samples; however, the concentrations of IL-1ß and TNF-α were the same as the unloaded samples. After the administration of a COX-2 selective inhibitor, the increased concentration of PGE2 by cyclic compressive loading was impeded, but the concentrations of IL-6 and IL-8 remained high. With dexamethasone, upregulation of PGE2, IL-6 and IL-8 was suppressed. CONCLUSION: These results could be useful in revealing the molecular mechanism of mechanical stress in vivo for a better understanding of the pathology and therapy of OA. Cite this article: Bone Joint Res 2014;3:280-8.

The spleen accumulates advanced glycation end products in the chicken: tissue comparison made with rat.

Glycation starts from nonenzymatic amino-carbonyl reaction that binds carbonyl group of reducing sugars to the amino group of amino acids. Glycation leads to further complex reactions to form advanced glycation end products (AGE). Because AGE are implicated in the gradual development of diabetic complications, tissue accumulation of AGE has been widely examined in various tissues of rats. Avian species are known to have high body temperature and blood glucose concentration compared with mammals. Although these characteristics enabled chickens to be used as experimental models for diabetes mellitus, the information of AGE accumulation in various tissues of chickens has not been limited so far. In the present study, therefore, the radioactive AGE prepared by reacting (14)C-glucose and amino acids were intravenously administrated, and comparison of tissue accumulation of (14)C-labeled AGE was made between chickens and rats. At 30 min after administration, tissues (18-20) were collected, and the radioactivity incorporated into tissues was determined. High levels of radioactivity per gram of tissue in the liver and kidney were observed in both rats and chickens. In chickens but not rats, a large amount of (14)C-labeled AGE incorporated into 1 g of spleen was observed, and the specific accumulation of AGE in the avian spleen might have a particular role in immune response in avian species.

Anemia amelioration by lactose infusion during trypanosomosis could be associated with erythrocytes membrane de-galactosylation.

African trypanosomosis is a potentially fatal disease that is caused by extracellular parasitic protists known as African trypanosomes. These parasites inhabit the blood stream of their mammalian hosts and produce a number of pathological features, amongst which is anemia. Etiology of the anemia has been partly attributed to an autoimmunity-like mediated erythrophagocytosis of de-sialylated red blood cells (dsRBCs) by macrophages. Lactose infusion to infected animals has proven effective at delaying progression of the anemia. However, the mechanism of this anemia prevention is yet to be well characterized. Here, the hypothesis of a likely induced further modification of the dsRBCs was investigated. RBC membrane galactose (RBC m-GAL) and packed cell volume (PCV) were measured during the course of experimental trypanosomosis in mice infected with Trypanosoma congolense (stb 212). Intriguingly, while the membrane galactose on the RBCs of infected and lactose-treated mice (group D) decreased as a function of parasitemia, that of the lactose-untreated infected group (group C) remained relatively constant, as was recorded for the uninfected lactose-treated control (group B) animals. At the peak of infection, the respective cumulative percent decrease in PCV and membrane galactose were 30 and 185 for group D, and 84 and 13 for group C. From this observed inverse relationship between RBCs membrane galactose and PCV, it is logical to rationalize that the delay of anemia progression during trypanosomosis produced by lactose might have resulted from an induction of galactose depletion from dsRBCs, thereby preventing their recognition by the macrophages.

Cryopreservation of nematode Caenorhabditis elegans in the adult stage.

Cryopreservation of nematode Caenorhabditis elegans in the adult stage is of importance as the nematode is a powerful research model organism. In this study, we applied the protocol previously established for cryopreservation of the L4 nematode to the adult one, and achieved a survival rate of 84%. When ice seeding was induced with bacteria P. syringae directly added to the nematode suspension instead of using a pre-cooled steel sticking needle, comparable survival rate was obtained after thawing. Moreover, a simple freezing device composed of a polystyrene foam box surrounded by a Dewar vessel put in a deep freezer was developed for a practical use. This simple method obtained a survival rate of 69 ± 4% for the adult nematode after thawing.

Pre-clinical evaluation of liposomal gene transfer to improve dermal and epidermal regeneration.

Liposomal gene transfer effectively enhances dermal and epidermal regeneration in burned rodents. To advance this treatment to clinical studies, we investigated the efficacy of liposomal gene transfer in a clinically relevant porcine wound model. Mimicking the clinical scenario, six female Yorkshire pigs (40-50 kg) received up to 12 burns of 50 cm(2) area that were fully excised and covered with skin autograft meshed at 4:1 ratio 24 h post-burn. Animals received control injections (empty liposomes), liposomes (DMRIE-C) containing 1 mg LacZ-cDNA, or liposomes (DMRIE-C) with 1 mg of platelet-derived growth factor (PDGF)-cDNA, or the naked PDGF gene. Serial biopsies were taken from different wound sites at multiple time points up to 12 days post-wounding. Transfection efficacy and transfection rate of LacZ and localization of beta-gal were determined by immunohistochemical and immunofluorescent techniques. RT-PCR and multiplex protein analysis (ELISA) were used to measure levels of growth factor mRNA transcribed and growth factor protein translated. Wound re-epithelialization and graft adhesion was evaluated using planimetric analysis and clinical scores. We found that peak transfection of liposomal beta-galactosidase occurred on day 2, with a fluorescence increase of 154% to baseline (P<0.001). Transfection intensity dropped to 115% above baseline on day 4 (P<0.001) and 109% on day 7. Immunohistochemistry showed a maximum transfection rate of 34% of cells in wound tissue. Gene transfer of liposomal PDGF-cDNA resulted in increased PDGF-mRNA and protein expression on days 2 and 4, and accelerated wound re-epithlialization as well as graft adhesion on day 9 (P<0.05). In this study, we showed that liposomal cDNA gene transfer is possible in a porcine wound model, and by using PDGF-cDNA we further showed that dermal and epidermal regeneration can be improved. These data indicate that liposomal gene transfer can be a new therapeutic approach to improve wound healing in humans.

Stimulatory effect of Coca-Cola on gastroduodenal HCO3- secretion in rats.

We examined the effect of various carbonated beverages, especially Coca-Cola, on the HCO3- secretion in the rat stomach and duodenum. Under urethane anaesthesia, a chambered stomach or a proximal duodenal loop was perfused with saline, and HCO3- secretion was measured at pH 7.0 using a pH-stat method and by adding 2 mM HCl. The amount of CO2 contained in these beverages was about 4-7 g/mL. Coca-Cola topically applied to the mucosa for 10 min significantly increased the HCO3- secretion in both the stomach and the duodenum. The HCO3- response in the duodenum was totally abolished by indomethacin and also partially inhibited by acetazolamide, an inhibitor of carbonic anhydrase. Likewise, the response in the stomach was also markedly inhibited by either acetazolamide or indomethacin. The mucosal application of Coca-Cola increased the PGE2 contents in both the stomach and the duodenum. Other carbonated beverages, such as sparkling water, Fanta Grape or cider, also increased the HCO3- secretion in these tissues. These results suggest that Coca-Cola induces HCO3- secretion in both the stomach and the duodenum, and these responses may be attributable to both the intracellular supply of HCO3- generated via carbonic anhydrase, and endogenous PGs, probably related to the acidic pH of the solution.

Clinical and prognostic significance of cytokine receptor expression in adult acute lymphoblastic leukemia: interleukin-2 receptor alpha-chain predicts a poor prognosis.

We quantitatively assessed the expression of cytokine receptors (interleukin-2 receptor (IL-2R), IL-3R, IL-4R, IL-5R, IL-6R, IL-7R, granulocyte-macrophage colony-stimulating factor R (GM-CSFR), G-CSFR, c-fms, c-mpl, c-kit and FLT3) in cells from 211 adults with acute lymphoblastic leukemia (ALL) by flow cytometry and determined their prevalence and clinical significance. Although all cytokine receptors were expressed to various degrees, the levels of IL-3R alpha-chain (IL-3Ralpha), IL-2Ralpha, IL-2Rbeta, IL-7Ralpha, common-Rgamma(gammac), c-mpl, c-kit and FLT3 exhibited a wide spectrum > or =2000 sites/cell. Among them, IL-3Ralpha, IL-2Ralpha and FLT3 were highly expressed in B-lineage ALL, whereas IL-7Ralpha, gammac and c-kit predominated in T-lineage ALL. Higher levels of IL-3Ralpha, IL-2Ralpha, c-kit and FLT3 correlated with the expression of CD13/33. Increased IL-2Ralpha levels related to the presence of Philadelphia chromosome (Ph), leukocytosis and shorter event-free survival (EFS). C-kit preferred in male. Elevated FLT3 levels correlated with age > or =60 years. Multivariate analysis in B-lineage ALL revealed only IL-2Ralpha (P=0.028) and Ph (P=0.020) as independent factors for EFS. These findings suggest that several cytokine receptors associated with certain cellular and clinical features, but IL-2Ralpha solely had a prognostic value and should be considered as a major prognostic factor for adult ALL that is comparable with Ph.

A simple protocol for preventing falls and fractures in elderly individuals with musculoskeletal disease.

UNLABELLED: Our protocol resulted in a significant prevention of falls and fractures in addition to marked improvements in the balance function. Intervention comprised a new balance exercise and quadriceps femoris exercise. Subjects were outpatients aged >or=65 years old with musculoskeletal disorders who had a result of or=65 years old and had a result of

Intraerythrocytic Plasmodium falciparum utilize a broad range of serum-derived fatty acids with limited modification for their growth.

Plasmodium falciparum causes the most severe form of malaria. Utilization of fatty acids in serum is thought to be necessary for survival of this parasite in erythrocytes, and thus characterization of the parasite fatty acid metabolism is important in developing a new strategy for controlling malaria. Here, we examined which combinations of fatty acids present in human serum support the continuous culture of P. falciparum in serum-free medium. Metabolic labelling and gas chromatography analyses revealed that, despite the need for particular fatty acids for the growth of intraerythrocytic P. falciparum, it can metabolize a broad range of serum-derived fatty acids into the major lipid species of their membranes and lipid bodies. In addition, these analyses showed that the parasite's overall fatty acid composition reflects that of the medium, although the parasite has a limited capacity to desaturate and elongate serum-derived fatty acids. These results indicate that the Plasmodium parasite is distinct from most cells, which maintain their fatty acid composition by coordinating de novo biosynthesis, scavenging, and modification (desaturation and elongation).

Concentration and microheterogeneity of acute-phase glycoproteins in patients with systemic lupus erythematosus.

PURPOSE: To determinate glycosylation of selected acute-phase glycoproteins (AGP, ACT, CP) and serum concentration of this proteins in Systemic Lupus Erythematosus (SLE) patients. PATIENTS AND METHODS: The study was carried out on 35 patients with active SLE and 15 healthy volunteers. The immunological measurements were performed at first day of hospitalisation, before receiving treatment. The concentration of CRP, AGP, ACT and CP were evaluated by electroimmunoassay using anti-AGP, anti-ACT, anti-CP antibodies. CRP levels were determined by radial immunodiffusion with anti-CRP antibodies. The microheterogeneity of the acute phase proteins was assessed by agarose affinity electrophoresis using Con A as a ligand, as was described by Bøg-Hansen. RESULTS: Between SLE patients and control group statistically significant differences (p < 0.01) were observed in serum concentration of all investigated parameters. There were no significant differences in serum acute-phase proteins levels with regards to patient's age, sex and disease activity. The reactivity coefficients: AGP-RC, ACT-RC, CP-RC in SLE patients were similar to the healthy group. The precipitate curves were similar in both groups. The main difference was in the area of the precipitant, which was bigger in the SLE patients. CONCLUSIONS: Configuration of analysis serum concentration and heterogeneity of acute-phase proteins is one of important diagnostic tests in SLE.

Rapid epidemiologic assessment of glucose-6-phosphate dehydrogenase deficiency in malaria-endemic areas in Southeast Asia using a novel diagnostic kit.

We recently reported a new rapid screening method for glucose-6-phosphate dehydrogenase (G6PD) deficiency. This method incorporates a new formazan substrate (WST-8) and is capable of detecting heterozygous females both qualitatively and quantitatively. Here, we report its evaluation during field surveys at three malaria centres and in malaria-endemic villages of Myanmar and Indonesia, either alone or in combination with a rapid on-site diagnosis of malaria. A total of 57 severe (45 males and 12 females) and 34 mild (five males and 29 females) cases of G6PD deficiency were detected among 855 subjects in Myanmar whilst 30 severe (25 males and five females) and 23 mild (six males and 17 females) cases were found among 1286 subjects in Indonesia. In all cases, severe deficiency was confirmed with another formazan method but due to limitations in its detection threshold, mild cases were misdiagnosed as G6PD-normal by this latter method. Our results indicate that the novel method can qualitatively detect both severely deficient subjects as well as heterozygous females in the field. The antimalarial drug, primaquine, was safely prescribed to Plasmodium vivax-infected patients in Myanmar. Our new, rapid screening method may be essential for the diagnosis of G6PD deficiency particularly in rural areas without electricity, and can be recommended for use in malaria control programmes.

Gene cloning and overexpression of two conjugated polyketone reductases, novel aldo-keto reductase family enzymes, of Candida parapsilosis.

The genes encoding two conjugated polyketone reductases (CPR-C1, CPR-C2) of Candida parapsilosis IFO 0708 were cloned and sequenced. The genes encoded a total of 304 and 307 amino acid residues for CPR-C1 and CPR-C2, respectively. The deduced amino acid sequences of the two enzymes showed high similarity to each other and to several proteins of the aldo-keto reductase (AKR) superfamily. However, several amino acid residues in putative active sites of AKRs were not conserved in CPR-C1 and CPR-C2. The two CPR genes were overexpressed in Escherichia coli. The E. coli transformant bearing the CPR-C2 gene almost stoichiometrically reduced 30 mg ketopantoyl lactone/ml to D-pantoyl lactone.

Influence of doxycycline on the epiphyseal plate cartilage of the rats in experimental osteoarthrosis, induced by iodoacetate.

In 36 Wistar rats with the iodoacetate-induced experimental osteoarthrosis (OA), effects of doxycycline, given orally, were determined on histochemical reactions of glycosaminoglycans (GAG) in the epiphyseal plate cartilage. The epiphyseal plate of rats with OA was reduced in height (especially the proliferative zone), cell columns were disorganized, many chondrocytes were irregular and polygonal, their nuclei were pycnotic, the intensity of GAG staining was irregular and predominantly reduced, which can be interpreted as signs of degeneration. A concomitant administration of doxycycline in the second group of rats prevented, to some extent, the negative effects of iodoacetate on chondrocytes and led to a more pronounced intensity of GAG reactions in the matrix of the epiphyseal plate.

Ultrastructure of the pineal gland after gamma-irradiation under conditions of inhibition of adrenocortical function.

Electron microscopy showed that whole-body gamma-irradiation in sublethal doses led to the appearance of injuries in pinealocytes, glial cells, and vessels of the pineal gland in rats. Limitation of the nonspecific effect of gamma-irradiation via inhibition of adrenocortical function with metopirone in physiological doses reduced the radiation-induced ultrastructural damage to the pineal gland.